DPP-4 inhibitor drugs appeared to have a null effect on risk for fatal and non-fatal cardiac events in two trials….

But the two drugs studied, alogliptin (Nesina) and saxagliptin (Onglyza), both DPP-4 (dipeptidyl peptidase-4) inhibitors, also didn’t reduce the risk of cardiovascular events.

The EXAMINE study which focused on alogliptin, included 5,380 type 2 diabetes patients within 3 months of hospitalization for acute MI or unstable angina. In that study, compared with placebo, treatment with alogliptin for up to 40 months did not increase the risk of a second acute event.

The second study, SAVOR TIMI 53, enrolled 16,492 diabetes patients who had a history of cardiovascular disease or were considered high risk for cardiovascular disease. Those patients were randomly assigned to either saxagliptin or placebo and followed for just over 2 years.

Again, the DPP-4 inhibitor neither increased nor decreased the risk of ischemic events. There was an increase, however, in hospitalizations for heart failure, said Deepak L. Bhatt, MD, MPH, of the TIMI Study Group, Brigham and Women’s Hospital, and Harvard Medical School in Boston.

At a press conference at the European Society of Cardiology meeting in Amsterdam, Bhatt said the data from SAVOR-TIMI and EXAMINE are likely to be interpreted very differently based on specialty. Bhatt added, "We had an investigators’ meeting last night, and the endocrinologists regarded these findings as great and they didn’t see the small imbalance in heart failure as a problem."

Cardiologists saw the results differently, according to Bhatt: "It didn’t improve outcomes and there was a 0.7% increase in heart failure over controls, although there was no signal of excess all-cause or cardiovascular mortality."

In an interview, Bhatt said he thought increased heart failure was most likely a class-effect for DPP-4 inhibitors but he noted that hospitalization for heart failure was a prespecified secondary endpoint for SAVOR-TIMI. "In clinical trials, as in life, if you look for something you find it. We looked for it."

He added that the excess heart failure was seen in patients who had a history of heart failure or were high risk for heart failure. White, speaking at the same press conference, said it was possible that the EXAMINE investigators would also find a heart failure signal as they move beyond their preliminary analysis. "We haven’t completed our analysis but there are many aspects of the EXAMINE data that are not in today’s presentation."

In the EXAMINE study, patients were randomized to alogliptin or placebo on top of standard therapy — usually metformin (alone or in combination with other agents), which was taken by about two-thirds of the patient. Almost half of the patients were taking sulfonylureas and roughly 30% were using insulin. Less than 3% were taking thiazolidinediones.

Most patients (71.4%) in the alogliptin treatment group received 25 mg daily, 25.7% took 12.5 mg, and 2.9% were dosed at 6.25 mg daily. Alogliptin patients achieved a mean 0.33 percentage-point decrease in glycated hemoglobin versus a 0.03-point increase in the placebo group. The investigators reported that the least-squares mean difference between the alogliptin and placebo groups was -0.36 percentage points (95% CI -0.43 to -0.26, P<0.001).

There were no significant differences in weight or lipid profiles between the two groups.

The alogliptin study was designed to evaluate noninferiority with a "prespecified noninferiority margin of 1.3 for the hazard ratio for the primary endpoint of death from cardiovascular causes, myocardial infarction, or nonfatal stroke," White and colleagues wrote.

After a median of 18 months, 305 patients in the alogliptin group versus 316 in the placebo arm — 11.3% versus 11.8% — had one of these endpoint events.

In the saxagliptin study, 613 patients taking the study drug reached the primary composite endpoint of cardiovascular death, myocardial infarction, or ischemic stroke, versus 609 patients assigned to placebo. Just as in the EXAMINE study, the study drug was given on top of standard therapy.